A study to evaluate the safety and efficacy of the tumor-targeting human antibody-cytokine fusion protein L19TNF plus standard temozolomide (TMZ) chemoradiotherapy in patients with newly diagnosed glioblastoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Philogen S.p.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2025-03-11

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Philogen S.p.A.

External identifiers

EU CT number

2024-516357-46-00

ClinicalTrials.gov

NCT04443010

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

The purpose of this study is to explore the safety profile and establish a recommended dose (RD) for phase II of the antibody-cytokine fusion protein L19TNF plus standard TMZ chemoradiotherapy in patients with newly diagnosed glioblastoma.
The primary objective of the phase II part of the study is to investigate the efficacy profile of the antibody-cytokine fusion protein L19TNF plus standard chemoradiotherapy in patients with newly diagnosed glioblastoma.
The primary objective of the phase IIb part of the study is to investigate the efficacy profile of the antibody-cytokine fusion protein L19TNF plus standard chemoradiotherapy in patients with newly diagnosed glioblastoma.

Secondary objectives 3

1. Secondary objective for Phase I is to assess the efficacy of L19TNF plus standard TMZ chemoradiotherapy in patients with newly diagnosed glioblastoma
2. Secondary objective for Phase II is to assess the efficacy and safety of L19TNF plus standard radiotherapy and TMZ in patients with newly diagnosed glioblastoma
3. Secondary objective for Phase IIb is to assess the efficacy and safety of L19TNF plus standard radiotherapy and TMZ in patients with newly diagnosed glioblastoma.

Conditions and MedDRA coding

Glioblastoma

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Male or female, age ≥18
2. Patients with histologically confirmed newly diagnosed glioblastoma
3. Karnofsky Performance Score (KPS) ≥ 70%
4. Documented negative test for HIV-HBV-HCV. For HBV serology, the determination of HBsAg and anti-HBcAg Ab is required. In patients with serology documenting previous exposure to HBV (i.e., anti-HBs Ab with no history of vaccination and/or anti-HBc Ab), negative serum HBV-DNA is required. For HCV, HCV-RNA or HCV antibody test is required. Subjects with a positive test for HCV antibody but no detection of HCV-RNA indicating no current infection are eligible
5. Female patients: negative pregnancy test for women of childbearing potential (WOCBP)* within 14 days of starting treatment. WOCBP must agree to use, from the screening to 6 months following the last study drug administration, highly effective contraception methods, as defined by the "Recommendations for contraception and pregnancy testing in clinical trials" issued by the Head of Medicine Agencies' Clinical Trial Facilitation Group (www.hma.eu/ctfg.html) and which include, for instance, progesterone-only or combined (estrogen- and progesterone-containing) hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormonereleasing systems, bilateral tubal occlusion or vasectomized partner. *Women of childbearing potential are defined as females who have experienced menarche, are not postmenopausal (12 months with no menses without an alternative medical cause) and are not permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy, or bilateral salpingectomy).
6. Male patients: male subjects able to father children must agree to use two acceptable methods of contraception throughout the study (e.g. condom with spermicidal gel). Double-barrier contraception is required.
7. Personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study
8. Willingness and ability to comply with the scheduled visits, treatment plan, laboratory tests and other study procedures

Exclusion criteria 32

1. Prior treatment for glioma, except surgery
2. Inability to undergo contrast-enhanced MRI
3. Intent to be treated with tumor-treating fields prior to progression
4. Known history of allergy to TNF or TMZ, any excipient in the study medication or any other intravenously administered human proteins/peptides/antibodies
5. Absolute neutrophil count (ANC) < 1.5 x 10^9/L, platelets < 100 x 10^9/L or haemoglobin (Hb) < 9.0 g/dl.
6. Chronically impaired renal function as indicated by creatinine clearance < 60 mL/min or serum creatinine > 1.5 ULN
7. Inadequate liver function (ALT, AST, ALP ≥ 2.5 x ULN or total bilirubin ≥ 2.0 x ULN).
8. INR > 1.5 ULN
9. Any severe concomitant condition which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol, in the opinion of the investigator
10. Active or history of autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent
11. History within the last year of cerebrovascular disease and/or acute or subacute coronary syndromes including myocardial infarction, unstable or severe stable angina pectoris
12. Heart insufficiency (> Grade II, New York Heart Association (NYHA) criteria)
13. Clinically significant cardiac arrhythmias or requiring permanent medication
14. Abnormal LVEF or any other abnormalities observed during baseline ECG and echocardiogram investigations that are considered as clinically significant by the investigator. Subjects with current or a history of QT/QTc prolongation are excluded
15. Uncontrolled hypertension
16. Known arterial aneurism at high risk of rupture
17. Ischemic peripheral vascular disease (Grade IIb-IV according to Leriche-Fontaine classification)
18. Medically documented history of, or active, major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or others), or patients with active severe personality disorders
19. Anxiety ≥ CTCAE Grade 3
20. Severe diabetic retinopathy such as severe non-proliferative retinopathy and proliferative retinopathy
21. Major trauma including major surgery (such as abdominal/cardiac/thoracic surgery) within 3 weeks of administration of study treatment
22. Known history of tuberculosis
23. Pregnancy or breast feeding
24. Requirement of chronic administration of high dose corticosteroids or other immunosuppressant drugs. Subjects must have been either off corticosteroids, or on a stable or decreasing dose ≤ 4 mg daily dexamethasone (or equivalent), for 7 days prior to start of chemoradiotherapy. Limited or occasional use of corticosteroids to treat or prevent acute adverse reactions is not considered an exclusion criterion
25. Presence of active and uncontrolled infections or other severe concurrent disease, which, in the opinion of the investigator, would place the patient at undue risk or interfere with the study
26. Concurrent malignancies unless the patient has been disease-free without intervention for at least 2 years
27. Growth factors or immunomodulatory agents within 7 days prior to the administration of study treatment
28. Serious, non-healing wound, ulcer, or bone fracture
29. Deep vein thrombosis, pulmonary embolism or other acute vascular events within 6 months
30. Anticoagulation therapy with P2Y12 antagonists (e.g., clopidogrel, ticagrelor) and vitamin K antagonists (e.g., phenprocoumon, warfarin)
31. Requirement of concurrent use of other anti-cancer treatments or agents other than study medication
32. Any recent live vaccination within 4 weeks prior to treatment or plan to receive vaccination during the study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. For Phase I the following primary safety endpoints will be considered: − Occurrence of dose limiting toxicity (DLT) assessed by frequency and grade of adverse events (AE) according to CTCAE v.5.0.
2. For Phase II the following primary endpoint will be considered: − Overall survival (OS) rate at 12 months (52 weeks).
3. For Phase IIb the following primary endpoint will be considered: − Overall survival (OS)

Secondary endpoints 3

1. For Phase I the following secondary safety endpoints will be considered: − Assessment of the formation of human anti-fusion protein antibodies (HAFA) against L19TNF. − Pharmacokinetic characterization of L19TNF. The following secondary efficacy endpoints will be considered: − Progression-free survival (PFS) based on iRANO criteria and a standardized MRI protocol. − Overall survival (OS) rate at 12 months (52 weeks). − OS. − Objective Response Rate (ORR, consisting of complete
2. For Phase II the following secondary efficacy endpoints will be considered: − PFS based on iRANO criteria and a standardized MRI protocol. − OS − ORR (consisting of CR and PR) at Week 10, at Week 22, at Week 34, at Week 46 and at Week 58 − BORR The following secondary safety endpoints will be considered: − Frequency and grade of AEs, SAE and DILI according to CTCAE v.5.0 − Assessment of the formation of HAFA against L19TNF − Pharmacokinetic characterization of L19TNF
3. For Phase IIb The following secondary efficacy endpoints will be considered: − PFS based on iRANO criteria based on standardized MRI protocol. − OS rate at 12 months (52 weeks) − ORR and DCR at Week 10, at Week 22, at Week 34, at Week 46 and at Week 58 − BORR The following secondary safety endpoint will be considered: − Frequency and grade of AEs, SAEs and DILI according to CTCAE v.5.0. − Assessment of the formation of HAFA against L19TNF. − PK characterization of L19TNF.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Philogen S.p.A.

Sponsor organisation

Philogen S.p.A.

Address

Piazza La Lizza 7

City

Siena

Postcode

53100

Country

Italy

Scientific contact point

Organisation

Philogen S.p.A.

Contact name

Teresa Hemmerle

Public contact point

Organisation

Philogen S.p.A.

Contact name

Teresa Hemmerle

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 25 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications